Trends in malaria cases, hospital admissions and deaths following scale-up of anti-malarial interventions, 2000-2010, Rwanda

ABSTRACT: BACKGROUND: To control malaria, the Rwandan government and its partners distributed insecticide-treated nets (ITN) and made artemisinin-based combination therapy (ACT) widely available from 2005 onwards. The impact of these interventions on malaria cases, admissions and deaths was assessed using data from district hospitals and household surveys. METHODS: District records of ITN and ACT distribution were reviewed. Malaria and non-malaria indictors in 30 district hospitals were ascertained from surveillance records. Trends in cases, admissions and deaths for 2000 to 2010 were assessed by segmented log-linear regression, adjusting the effect size for time trends during the pre-intervention period, 2000-2005. Changes were estimated by comparing trends in post-intervention (2006-2010) with that of pre-intervention (2000-2005) period. All-cause deaths in children under-five in household surveys of 2005 and 2010 were also reviewed to corroborate with the trends of deaths observed in hospitals. RESULTS: The proportion of the population potentially protected by ITN increased from nearly zero in 2005 to 38% in 2006, and 76% in 2010; no major health facility stock-outs of ACT were recorded following their introduction in 2006. In district hospitals, after falling during 2006- 2008, confirmed malaria cases increased in 2009 coinciding with decreased potential ITN coverage and declined again in 2010 following an ITN distribution campaign. For all age groups, from the pre-intervention period, microscopically confirmed cases declined by 72%, (95% Confidence Interval [CI], 12-91%) in 2010, slide positivity rate declined 58%, (CI, 47%-68%), malaria inpatient cases declined 76% (CI, 49%-88%); and malaria deaths declined 47% (CI, 47%-81%). In children below five years of age, malaria inpatients decreased 82% (CI, 61%-92%) and malaria hospital deaths decreased 77% (CI, 40%-91%). Concurrently, outpatient cases, admissions and deaths due to non-malaria diseases in all age groups either increased or remained unchanged. Rainfall and temperature remained favourable for malaria transmission. The annual all-cause mortality in children under-five in household surveys declined from 152 per 1,000 live births during 2001-2005, to 76 per 1,000 live births in 2006-2010 (55% decline). The five-year cumulative number of all-cause deaths in hospital declined 28% (8,051 to 5,801) during the same period. CONCLUSIONS: A greater than 50% decline in confirmed malaria cases, admissions and deaths at district hospitals in Rwanda since 2005 followed a marked increase in ITN coverage and use of ACT. The decline occurred among both children under-five and in children five years and above, while hospital utilization increased and suitable conditions for malaria transmission persisted. Declines in malaria indicators were more striking than in the older age groups. The resurgence in cases associated with decreased ITN coverage in 2009 highlights the need for sustained high levels of anti-malarial interventions in Rwanda and other malaria endemic countries.     

Effect of pre-weaning concentrate supplementation on peripheral distribution of leukocytes, functional activity of neutrophils, acute phase protein and behavioural responses of abruptly weaned and housed beef calves

Background  

The effect of pre-weaning concentrate supplementation on peripheral distribution of leukocytes, functional activity of neutrophils, acute phase protein response, metabolic and behavioural response, and performance of abruptly weaned and housed beef calves was investigated. Calves were grazed with their dams until the end of the grazing season when they were weaned and housed (day (d) 0) in a concrete slatted floor shed, and offered grass silage ad libitum plus supplementary concentrates. Twenty-six days prior to weaning and housing, 20 singled suckled, pure-bred Simmental male (non-castrated), (n = 10, m) and female (n = 10, f) calves were assigned to one of two treatments (i) concentrate supplement (CS: n = 10 (5 m and 5 f), mean age (s.d.) 201 (12.8) d, mean weight (s.d.) 258 (20.2) kg) or (ii) no concentrate supplement (controls) (NCS: n = 10, (5 m and 5 f), mean age (s.d.) 201 (13.4) d, mean weight (s.d.) 257 (19.6) kg) pre-weaning.     

Synthesis, biological activity and comparative analysis of DNA binding affinities and human DNA topoisomerase I inhibitory activities of novel 12-alkoxy-benzo[c]phenanthridinium salts

New antitumor 12-alkoxy-benzo[c]phenanthridinium derivatives were obtained in high yields through multistep syntheses. Analysis of DNA binding and human DNA topoisomerase I inhibitory activities demonstrates that new compounds, combining 2, 6, and 12 substitutions, interact strongly with DNA and exhibit important topoisomerase I inhibition. The cytotoxicities against solid tumor cell lines are also determined and compared with those for fagaronine and ethoxidine.     

The application of foaming for the recovery of Surfactin from B. subtilis ATCC 21332 cultures

Foaming, a proficient method for the recovery of surface active solutes from dilute solutions, was successfully applied for the concentration of the lipopeptide biosurfactant Surfactin from B. subtilis ATCC 21332 cell culture broths. Foaming was only partially successful in concentrating Surfactin when applied as a separate semi-batch unit downstream of the cell culture stage. Surfactin partitioned strongly into the foam during the latter stages of the semi-batch process, where enrichments of over 50 could be obtained. However, simultaneous high enrichments and recoveries of Surfactin could not be obtained as the majority of Surfactin (around 70% of the total recovered) was produced at a low concentration during the early stages of foaming. Foam fractionation was considered for both cell free and cell containing broths; the presence of cells increased the foamability of the solution and therefore yielded more dilute Surfactin preparations. More favourable recovery and enrichment of Surfactin occurred when foaming was integrated with the cell culture stage. The use of low stirrer speeds was essential in producing foam at a controlled rate. By collecting fractions of the foam produced between 10 and 30 hours, from systems stirred at 166 and 146 rpm, a highly concentrated Surfactin extract could be obtained. The Surfactin concentration in the foam was 1.22 and 1.67 g l(-1) respectively, which represented enrichments and percent recoveries of over 60. This study points to the utility of foaming as a method for the recovery of surface-active fermentation products, particularly when used in an integrated production/recovery system.     

Visualization of SV2A conformations in situ by the use of Protein Tomography

The synaptic vesicle protein 2A (SV2A), the brain-binding site of the anti-epileptic drug levetiracetam (LEV), has been characterized by Protein Tomography™. We identified two major conformations of SV2A in mouse brain tissue: first, a compact, funnel-structure with a pore-like opening towards the cytoplasm; second, a more open, V-shaped structure with a cleft-like opening towards the intravesicular space. The large differences between these conformations suggest a high degree of flexibility and support a valve-like mechanism consistent with the postulated transporter role of SV2A. These two conformations are represented both in samples treated with LEV, and in saline-treated samples, which indicates that LEV binding does not cause a large-scale conformational change of SV2A, or lock a specific conformational state of the protein. This study provides the first direct structural data on SV2A, and supports a transporter function suggested by sequence homology to MFS class of transporter proteins.     

Structure-activity analysis of ginkgolide binding in the glycine receptor pore

Ginkgolides, active constituents of Ginkgo biloba extracts, potently block the glycine receptor chloride channel (GlyR). Ginkgolides A, B, C and J are structurally similar, varying only by the presence or absence of oxygens at their R1 and R2 positions. The aim of this study was to understand how variable ginkgolide groups bind to pore-lining 2' and 6' residues in the α1 GlyR. Ginkgolide potency was not affected by G2'A or G2'S mutations, suggesting 2' residues are not important for ginkgolide coordination. Analysis of the α1^T6'S GlyR suggests that ginkgolides bind to this receptor via hydrogen bonds between T6'S and ginkgolide R1 hydroxyls. The abolition of block by the T6'A and T6'V mutations but not by the T6'S mutation implies the existence a second transmembrane domain α-helical kink formed by hydrogen bonding between 6' threonine and serine sidechains and backbone carbonyl oxygens. We also found that ginkgolide A binds in different orientations in the closed and open states of a mutant GlyR, possibly reflecting its enhanced flexibility relative to other ginkgolides. Together these results indicate that small variations in ginkgolide structure or pore structure can lead to drastic potency variations. This property may be exploited to create improved pharmacological probes for discriminating among anionic Cys-loop receptor isoforms with 6' structural variations.     

The major histocompatibility complex class II alleles Mamu-DRB1*1003 and -DRB1*0306 are enriched in a cohort of simian immunodeficiency virus-infected rhesus macaque elite controllers

The role of CD4(+) T cells in the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication is not well understood. Even though strong HIV- and SIV-specific CD4(+) T-cell responses have been detected in individuals that control viral replication, major histocompatibility complex class II (MHC-II) molecules have not been definitively linked with slow disease progression. In a cohort of 196 SIVmac239-infected Indian rhesus macaques, a group of macaques controlled viral replication to less than 1,000 viral RNA copies/ml. These elite controllers (ECs) mounted a broad SIV-specific CD4(+) T-cell response. Here, we describe five macaque MHC-II alleles (Mamu-DRB*w606, -DRB*w2104, -DRB1*0306, -DRB1*1003, and -DPB1*06) that restricted six SIV-specific CD4(+) T-cell epitopes in ECs and report the first association between specific MHC-II alleles and elite control. Interestingly, the macaque MHC-II alleles, Mamu-DRB1*1003 and -DRB1*0306, were enriched in this EC group (P values of 0.02 and 0.05, respectively). Additionally, Mamu-B*17-positive SIV-infected rhesus macaques that also expressed these two MHC-II alleles had significantly lower viral loads than Mamu-B*17-positive animals that did not express Mamu-DRB1*1003 and -DRB1*0306 (P value of <0.0001). The study of MHC-II alleles in macaques that control viral replication could improve our understanding of the role of CD4(+) T cells in suppressing HIV/SIV replication and further our understanding of HIV vaccine design.     

Early life-history processes in benthic octopus: Relationships between temperature, feeding, food conversion, and growth in juvenile Octopus pallidus

Initial growth in cephalopods is exponential, making early life-history critical in determining growth trajectories. Few captive studies have however examined the early life-history of cephalopods in fluctuating temperatures as would be encountered in the wild. This study investigates the relationship between early growth and the significant factors affecting growth, namely food intake, food conversion and fluctuating environmental temperatures. Pale octopus (Octopus pallidus) hatchlings were reared in captivity under either a warming or cooling temperature regime. Individual variations and periodicity in feeding rates (F_r), food conversion rates (C_r), growth rates (G_r), and the relationship between these variables and temperature were examined weekly. Food conversion rates were variable between individuals but also within individual octopus, which exhibited large fluctuations in C_r over time, exceeding 100% d^− 1 in one instance. Although individual F_r, C_r and G_r displayed fluctuations over time, there was no evidence of periodicity for any of the variables. Changes in temperature were not significantly correlated to changes in F_r, C_r or G_r. Feeding rate did not appear to influence growth rate or food conversion rate. Food conversion rate was negatively correlated to feeding rate in the same week, and positively correlated to growth rate. Short periods of low or no food consumption were common and the high values obtained for food conversion rate for some individuals suggest that octopus can grow substantially with little or no food intake. Individual variability observed in octopus growth may be dependent on the growth mechanism involved, specifically a fine balance between the continuous hyperplasic and hypertrophic growth found in cephalopods.     

IL-23 promotes maintenance but not commitment to the Th17 lineage

IL-23 plays a critical role establishing inflammatory immunity and enhancing IL-17 production in vivo. However, an understanding of how it performs those functions has been elusive. In this report, using an IL-17-capture technique, we demonstrate that IL-23 maintains the IL-17-secreting phenotype of purified IL-17(+) cells without affecting cell expansion or survival. IL-23 maintains the Th17 phenotype over multiple rounds of in vitro stimulation most efficiently in conjunction with IL-1beta. However, in contrast to Th1 and Th2 cells, the Th17 phenotype is not stable and when long-term IL-23-stimulated Th17 cultures are exposed to Th1- or Th2-inducing cytokines, the Th17 genetic program is repressed and cells that previously secreted IL-17 assume the cytokine secreting profile of other Th subsets. Thus, while IL-23 can maintain the Th17 phenotype, it does not promote commitment to an IL-17-secreting lineage.